The goal of this proposed work is to analyze the role of the deacetylase Sirtuin 1 (SIRT1) in Amyotrophic Lateral Sclerosis (ALS) and to investigate whether changes in the acetylation of SIRT1 targets may be a useful biomarker in patients with this disease. SIRT1 has been shown to be protective in a number of neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's disease and small molecule activators and inhibitors of SIRT1 have entered phase I and phase II clinical trials the United States and Europe. Preliminary results using a transgenic mouse model for ALS indicate that overexpressing SIRT1 may be protective against motor neuron disease and the mechanism for this phenomenon is under investigation. A variety of biochemical and molecular techniques will be used to investigate whether SIRT1 affects ALS disease progression by deacetylating PGC1alpha, LXRbeta, TDP43 and other sirtuin targets. The effect of SIRT1 overexpression on proteasomal function will also be explored. Because all of the ALS mouse lines model rare familial mutations of the disease, we will also analyze clinical postmortem samples to learn whether protein changes observed in the mouse studies are generalizable to patients with sporadic ALS. The work proposed here will be conducted under the mentorship of Dr. Leonard Guarente, who discovered the link between sirtuins and aging in 1999 and was the first to report its novel catalytic activity the following year. The Guarente laboratory has gradually shifted its focus from studies on lifespan in lower organisms to the role of the sirtuin proteins in neurodegeneration, cancer and other diseases of aging. The applicant is an M.D. /Ph.D. who is board certified in clinical pathology and committed to spending a minimum of 80% of her time as a researcher throughout her career. She currently holds a joint appointment as instructor at Brigham and Women's Hospital (BWH) and postdoctoral affiliate at MIT. Her long-term goal is to direct a laboratory that performs basic and translational research using mouse models and human samples to study neurodegenerative diseases of aging. It is anticipated that the project will yield important insight into new diagnostic and therapeutic strategies for ALS and will prepare the candidate for a career as an independent investigator.